PROJECT SUMMARY Salmonellosis continues to be a major Public Health challenge. Salmonella enterica encompasses multiple serovars that are associated with distinct pathogenic features and host specificities. S. enterica serovar Typhi for example, is the cause of typhoid fever, a systemic disease of humans that leads to an estimated 200,000 deaths worldwide. In contrast, the broad host S. Typhimurium causes limited gastroenteritis and is one of the most common causes of food-borne illnesses in the industrialized world. The pathogenicity of all S. enterica serovars requires the activity of two type III protein secretion systems (T3SS) encoded within their pathogenicity islands 1 and 2. These T3SSs direct the translocation of a battery of bacterial effectors with the capacity to modulate a variety of cellular functions. Working in conjunction with one another, these effectors modulate actin cytoskeleton dynamics, host-cell gene expression, vesicle trafficking, and innate and acquired immune responses, thus allowing Salmonella to gain access to and replicate within host cells, avoid host defenses, induce intestinal inflammation, and reach deeper tissues. Despite the significant progress, however, much remains to be learned as the biochemical activities and/or relevant cellular targets of many Salmonella effectors remain uncharacterized. The objectives of this proposed research is to study the functional interface between Salmonella and its host shaped by the activities of T3SS effectors. More specifically, we intend to define the mechanisms by which the Salmonella T3SS effectors modulate signaling pathways leading to intestinal inflammation, a critical step in its pathogenesis. In addition, we will study the mechanism by which a recently discovered cell intrinsic host defense pathway restricts Salmonella intracellular replication. These studies will advance the understanding of the cell biology of Salmonella enterica infections and potentially facilitate the development of novel therapeutic and prevention strategies. Furthermore, these studies may establish new paradigms of host-pathogen interactions that may be applicable to other important pathogens that have evolved close associations with their respective hosts.